The overarching goal of this project is to define the contribution of glia to Parkinson?s disease (PD) and thereby generate novel glial therapeutic targets. To do this, I will use an innovative approach that combines the power of Drosophila genetics with state of the art human cell culture systems. Specifically, I will identify novel glial modifiers of neuronal ?-synuclein toxicity using a novel dual bipartite Drosophila ?-synucleinopathy transgenic system, confirm the expression of these modifiers in human PD brain tissue, and then determine their mechanism using both Drosophila models and human cells by co-culturing human iPSC-derived astrocytes and neurons. In completing the project, I will gain essential training in these diverse, state of the art model systems, which will fill gaps in my current skillset. The career development plan has been carefully crafted to support my goal of becoming a leading independent investigator in PD research, simultaneously directing a research team and treating patients with PD. The plan includes an outstanding mentorship team composed of internationally known experts in neurodegeneration and Parkinson?s disease: Dr. Mel Feany, Dr. Dennis Selkoe, Dr. Clemens Scherzer, and Dr. Vikram Khurana. The senior members of my membership team have an outstanding record of training physician scientists who rise to prominence in the field of neurodegeneration. The institutional resources available through Brigham and Women?s Hospital and Harvard Medical School are world class and will support my career in an environment that can foster high impact contributions and collaborative endeavors. Upon successful completion of this project, I will be ideally positioned to be an independent investigator, answering fundamental questions about the contribution of glia to PD through the unique expertise I have gained in glial neurobiology in Drosophila and humans.